Although much is known about the oncogenic functions of chimeric
Ewing sarcoma (EWS) fusion
proteins that result from
chromosomal translocations, the cellular role of the normal
EWS protein is not well characterized. We have previously identified a WD domain-containing
protein, serine-threonine kinase receptor-associated
protein (STRAP), which inhibits
transforming growth factor beta (
TGF-beta) signaling through interaction with receptors and Smad7 and promotes growth and enhances tumorigenicity. Here, we report the interaction between STRAP and EWS using matrix-assisted
laser desorption/ionization, time-of-flight and tandem mass spectrometry. Although STRAP is localized in both cytoplasm and nucleus, nuclear STRAP colocalizes and associates specifically with EWS in the nucleus through its NH(2) and COOH termini. We have found that normal
EWS protein is up-regulated in human
cancers, which correlates with the up-regulation of STRAP in 71% of
colorectal cancers and 54% of
lung cancers, suggesting a cooperative role of these two
proteins in human
cancers.
TGF-beta has no effect on STRAP and EWS interaction. However, EWS, like STRAP, attenuates
TGF-beta-dependent transcription. STRAP inhibits EWS-dependent p300-mediated transactivation of EWS target genes, such as ApoCIII and c-fos, in a
TGF-beta-independent manner. Interestingly, we have shown that STRAP blocks the interaction between EWS and p300, whereas the complex formation between STRAP and EWS is not affected by p300. These results suggest that STRAP inhibits the transactivation function of EWS by displacing p300 from the functional transcriptional complex. Thus, this study provides a novel
TGF-beta-independent function of STRAP and describes a mechanism by which STRAP regulates the function of oncogenic
EWS protein.